1. Field of the Invention
The field of this invention is treatment of neoplasia.
2. Background of the Invention
Natural killer cells attack many tumor cell lines in vitro, and, after activation, can attack primary tumor cells1. NK cells have therefore long been thought to be involved in tumor surveillance and to be an important part of anti-tumor immunity2-8, but the basis for the interaction between NK cells and tumor targets remains largely unknown. Recently, the stimulatory lectin-like NKG2D receptor has been characterized9-15. In mice, the receptor is expressed by NK cells, activated CD8+ T cells and activated macrophages, and receptor engagement can stimulate or costimulate these cells14-15. Several distinct families of cell surface ligands for NKG2D have been identified, all of which are distantly related to class I MHC molecules13-16. These ligands are often expressed at high levels by tumor cells, but not by normal cells in mature animals14, 15, 17, 18. While the prevalence of these ligands on highly tumorigenic cells suggests they might provide a target for therapeutic intervention, it also suggested that their presence is insufficient to provoke a host rejection of the tumor.
We disclose here the remarkable development of methods whereby, contrary to expectations, NKG2D ligands can indeed be exploited to provoke a host response to inhibit tumor growth. Our methods are also effective prophylactically, to inhibit tumor formation, and remarkably, are effective against both tumors expressing the ligands and tumors which do not.
Relevant Literature
Diefenbach, et al., Nature Immunology 1, 119-26 (2000) describe ligands for the mNKG2D receptor and activation of NK cells and macrophages in mice. Relevant information was disclosed at the Keystone Conference, Jan. 1, 2001 and Gordon Conference, Feb. 1, 2001. Smyth, et al., Nature Immunology 2, 293-9 (2001) discuss therapeutic immunity to cancer. Li, et al., Nature Immunology 2, 443-51 (2001) report MICA as a stress inducible ligand for NKG2D and the crystal structure of the complex. A CTLA-4 blockade to enhance immune response is reported in U.S. Pat. No. 6,051,227.
The invention provides methods for inhibiting tumor growth. The methods may be therapeutically applied to a mammalian host expressing native NKG2D and determined to harbor a tumor arising in situ and comprising tumor cells, and/or prophylactically applied to a mammalian host expressing native NKG2D and determined to be predisposed to harboring a tumor arising in situ.
The general methods involve administering to the mammalian host a composition comprising a multivalent NKG2D-binding agent, wherein the administering step is effective to inhibit growth of the tumor; and detecting a resultant inhibition of growth of the tumor.
In particular embodiments, the tumor cells provide one or more of the following characteristics: are melanoma cells; present downregulated MHC class I proteins; express a native NKG2D ligand; express a substantially undetectable amount of NKG2D ligand; are substantially non-immunogenic; are highly metastatic; and are highly tumorigenic.
In a particular embodiment, the administering is remote from the tumor.
In particular embodiments, the agent comprises: a multivalent NKG2D-specific antibody; a multivalent NKG2D ligand comprising a plurality of covalently linked natural NKG2D ligand moieties; a multivalent NKG2D ligand comprising a plurality of non-covalently linked natural NKG2D ligand moieties, wherein the moieties are restricted to a common presenting surface, particularly wherein the common presenting surface may be of a host-compatible (such as host- or tumor-derived) cell transformed to express the ligand moieties; and/or a multivalent NKG2D ligand comprising a plurality of natural NKG2D ligand moieties, such as MICA, MICB and ULBP ligand moieties.
Accordingly, cancer treatment is provided by administering binding agents, such as ligands for the NKG2D receptor in vivo to activate immune cells present in a host to enhance the immune response to cancer cells. The ligands are presented by themselves or in conjunction with other compounds that may serve as immune system activators and/or provide for greater specificity for the target. The ligands are administered in a form that results in the aggregation or multimerization of the receptor, such as multivalent form, such as bound to membranes, linked together, or expressed on genetically modified cells.